EP0806944A1 - Biodegradable sustained release preparation for treating periodontitis - Google Patents
Biodegradable sustained release preparation for treating periodontitisInfo
- Publication number
- EP0806944A1 EP0806944A1 EP95934323A EP95934323A EP0806944A1 EP 0806944 A1 EP0806944 A1 EP 0806944A1 EP 95934323 A EP95934323 A EP 95934323A EP 95934323 A EP95934323 A EP 95934323A EP 0806944 A1 EP0806944 A1 EP 0806944A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- medicine
- weight
- sustained release
- preparation
- chitosan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
Definitions
- the present invention relates to a biodegradable sustained release preparation for treating periodontitis. More specifically, this invention relates to a biodegradable sustained release preparation for treating periodontitis characterized in that the core, which is further coated with chitosan, of the preparation contains medicine and polysaccharide, i.e. sodium alginate.
- Periodontitis an inflammation of periodontium caused by anaerobic bacteria, is a periodontal disease exacerbated from gingivitis. Because periodontitis destructs collagen supporting alveolodental membrane and dissolves alveoru, periodontal ligament are dissociated and periodontal cyst, an important clinical symptom, is invaded. In serious symptom, teeth are lost.
- the pathogenetic bacteria causing periodontitis are mostly gram-negative anaerobic bacteria. Those bacteria destruct desmoplasm and periodontal ligament of alveolodental membrane a side effect of migrating poly orphonuclear cell depravates inflammation.
- the general therapy of periodontitis in the prior art includes apparatotherapy such as scaling, curettage or root planing.
- these therapies are used only as a supplementary method due to high recurrens. Therefore, in order to treat periodontitis, pharmacotherapy have to be used primarily.
- examples of pharmacotherapy includes antibiotic therapy for controlling gram-anaerobic bacteria and therapy of using antiphlogistic for laxation of inflammation.
- tetracycline-type medicines are preferred because they are used widely and have low toxicity for human beings. Since the MIC(minimum inhibition concentration) 90% value is 8 ⁇ g/ml, the effectiveness of these medicines is high enough to be maintained for 6 months per only a dose.
- antibiotic therapy in case of systemic medication, since an excessive amount of antibiotics have to be used for maintaining the effective concentration of medicine in the palatal bursa of gingiva, the side effect and manifestation of tolerance are occurred.
- oral irrigation is preferred in order to administrate the antibiotics topically.
- this therapy is unsuitable because the medicine can not satisfactorily pass through periodontal cyst.
- a method of direct injection of medicine with a syringe is only effective for a short-term therapy but not for a long-term therapy.
- collagen film containing tetracycline developed by Minabe etc. is a biodegradalde preparation of which effective concentration is prolonged over 10 days in palatal bursa of gingive, it has a disadvantage of causing immunoreaction due to hetero antigen-protein.
- filamentous devices containing medicine described in USP-3,417, 179, USP-2,667,443, USP-2,748,781 and USP-3,942,539 and hollow fiber device described in USP-4,175,326, both made of cellulose acetate, are effective in inclusion of medicine but not in control of releasing medicine.
- the present invention has an object to provide an advanced biodegradable sustained release medicine carrier.
- this invention provides a biodegradable sustained release preparation of which the core contains sodium alginate unit and medicine, and the surface thereof is coated with chitosan. Accordingly, the preparation of the present invention can maximize the inclusion effect of medicine into periodontal cyst and slowly release the medicine for a prescribed period by preparing microcapsules with polysaccharide.
- Figure 1 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 1.
- Figure 2 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 2.
- Figure 3 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 3.
- Figure 4 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 4.
- Figure 5 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 5.
- Figure 6 is a graph showing the comparison of release of medicine from the biodegradable sustained release preparation in accordance with the present invention to the release from a conventional product, Periocline.
- the present inventors prepared anionic polysaccaride microspheres containing medicine by using gelating power of polysaccaride and then coating thereof with a cationic polymer, i.e. chitosan to provide microcapsules.
- microspheres are prepared by gelation of a solution of sodium alginate with bivalent cation.
- the product is reacted with cationic polymer of chitosan, of which ionic character is counter to alginic acid, to form a film to make microcapsules.
- the elution of medicine of the preparation produced by the present method is controlled by film of chitosan.
- chitosan After releasing medicine, chitosan is dissociated by enzyme in mouth such as lysozyme.
- the role of polysaccharide, i.e. sodium alginate as a unit of preparation is inclusion of medicine into the preparation, and the role of chitosan is controlling the release of medicine.
- the concentration of chitosan is about 2% by weight/volume. If the concentration is far lower than 2% by weight/volume, it is impossible to control the release of medicine for 7 days, where the effect of the coated layer decreases by viscous chitosan if the concentration is far higher than 2% by weight/volume.
- the size of the microparticle containing medicine is desirably about 70 ⁇ m. If the size is far larger than 70 ⁇ m, injection from a container for applying the preparation into periodontal cyst is difficult, where the medicine releases in short period if the size is far smaller than 70 ⁇ m.
- the medicine used in the preparation of the present invention includes tetracycline hydrochloride, tetracycline bases, minocycline hydrochloride, ibuprofen or flubiprofen, and, in particular, minocycline hydrochloride is desirable.
- the content of the above medicine is preferably 2% to 10% by weight each with respect to the weight of the final formulation. If the content is lower than 2% by weight, it is impossible to maintain the released concentration of medicine to MIC, where the medicine may cause toxicity if the content exceeds 10% by weight.
- a 2% by weight/volume solution of sodium alginate containing medicine was added dropwise to a 1.5% by weight/volume aqueous solution of calcium chloride by using a droplet extruser nozzle through which a compressed gas was passing. After dropping, the mixture was gellated for 5 minutes. Subsequent to washing and filtering the resultant gelated particles, collected microparticles were coated with 2% by weight/volume solution of chitosan for 10 minutes.
- the medicine was minocycline hydrochloride, and the content of the above medicine was 2%, 5% or 10% by weight each with respect to the weight of the final formulations.
- the experiment of releasing the medicine from the microspheres prepared was carried out by the following steps: 50 mg of microspheres put in a basket was added to 50 ml of HEPES buffer solution and the resultant mixture was shaked at 37 ⁇ 0.5, 15 rpm; the samples were collected in a predetermined duration for 7 days and quantatively analysed by the use of UV spectrophotometer.
- FIG. 1 shows the release pattern where the content of medicine was 2%, 5% or 10% by weight/volume each. It is found that the release of the medicine increases proportionally to the content of medicine. The initial rate of release increased with the increase of medicine content, and then the release of medicine increased with constant rate.
- Example 2 Coated microspheres were prepared in accordance with Example 1 but a 2% by weight/volume solution of sodium alginate without containing medicine. The coated microsperes were then immersed in a medicinal solution, and it was left alone for 24 hours and dried to make the content of medicine with respect to the final formulation become 2%, 5% or 10% by weight.
- Microspheres prepared in Example 2 were immersed in 0.5%, 1% or 2% by weight/volume solution of minocycline hydrochloride respectively so that the swelling load was carried out.
- the content of the medicine was made 2%, 5% or 10% by weight each with respect to the weight of the final formulation, dependent upon the concentration.
- the time period for swelling load was 24 hours.
- microparticles encapsulating medicine was coated with a 2% by weight/volume solution of chitosan.
- Example 4 A solution of sodium alginate containing medicine was emulsion-dispersed in organic solvent containing a surfactant. To the resultant dispersion was added dropwise a solution of calcium chloride so that microparticles of gel was formed.
- the organic solvent was a 3:1 mixture of hexane and chloroform, and the surfactant used was Span, a surfactant of sorbitan monostearate. The concentration of the surfactant was 0.4% by weight/volume with respect to the dispersion medium.
- the resultant microparticles were collected, washed and filtered. Then a 2% by weight/volume solution of chitosan was added thereto to form a coating.
- the medicine was minocycline hydrochloride and the content of the above medicine was 2%, 5% or 10% by weight each with respect to the weight of the final formulation.
- Example 4 microparticles of sodium alginate without containing medicine were prepared and these were immersed in each medicinal solutions with different concentration to be swelling loaded.
- the medicine was minocycline hydrochloride and each content of the above medicine was 2%, 5% or 10% by weight with respect to the weight of the final formulations.
- the time period for swelling load was 24 hours. After washing and filtering, the microparticles encapsulating the medicine were coated with a 2% by weight/volume solution of chitosan.
- the biodegradable sustained release preparation according to the present invention shows gradual increase of releasing rate from the period after first day to the seventh day (See Figure 6) .
- the present invention provides a biodegradable sustained release preparation which can slowly release the antibiotic in periodontal cyst in a long-term period.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nutrition Science (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a biodegradable sustained release preparation for treating periodontitis, especially containing polysaccharide. The core of the preparation according to the present invention consists of medicine and polysaccharide, i.e. sodium alignate, and is coated with cationic chitosan. By the function of chitosan building the coating of the preparation, the medicine is slowly released, and the carrier is completely decomposed by lysozyme in vivo after the release of the medicine.
Description
BIODEGRADABLE SUSTAINED RELEASE PREPARATION FOR TREATING PERIODONTITIS
BACKGROUND OF THE INVENTION Field of the Invention
The present invention relates to a biodegradable sustained release preparation for treating periodontitis. More specifically, this invention relates to a biodegradable sustained release preparation for treating periodontitis characterized in that the core, which is further coated with chitosan, of the preparation contains medicine and polysaccharide, i.e. sodium alginate.
Periodontitis, an inflammation of periodontium caused by anaerobic bacteria, is a periodontal disease exacerbated from gingivitis. Because periodontitis destructs collagen supporting alveolodental membrane and dissolves alveoru, periodontal ligament are dissociated and periodontal cyst, an important clinical symptom, is invaded. In serious symptom, teeth are lost. The pathogenetic bacteria causing periodontitis are mostly gram-negative anaerobic bacteria. Those bacteria destruct desmoplasm and periodontal ligament of alveolodental membrane a side effect of migrating poly orphonuclear cell depravates inflammation.
Description of the Prior Art
The general therapy of periodontitis in the prior art includes apparatotherapy such as scaling, curettage
or root planing. However, these therapies are used only as a supplementary method due to high recurrens. Therefore, in order to treat periodontitis, pharmacotherapy have to be used primarily. Examples of pharmacotherapy includes antibiotic therapy for controlling gram-anaerobic bacteria and therapy of using antiphlogistic for laxation of inflammation. Among the various antibiotics, tetracycline-type medicines are preferred because they are used widely and have low toxicity for human beings. Since the MIC(minimum inhibition concentration) 90% value is 8 μg/ml, the effectiveness of these medicines is high enough to be maintained for 6 months per only a dose. With regard to antibiotic therapy, in case of systemic medication, since an excessive amount of antibiotics have to be used for maintaining the effective concentration of medicine in the palatal bursa of gingiva, the side effect and manifestation of tolerance are occurred.
Alternatively, in case of the generally preferred topical therapy, oral irrigation is preferred in order to administrate the antibiotics topically. However, this therapy is unsuitable because the medicine can not satisfactorily pass through periodontal cyst. Also, a method of direct injection of medicine with a syringe is only effective for a short-term therapy but not for a long-term therapy.
In these circumstances, a sustained release
preparation which can slowly release medicine in periodontal cyst by inserting a carrier into periodontal cyst has been recently developed in order to solve these problems. This method has been disclosed in the documents as follows: USP-3,911,099 capsules and tablets of prolonged effects; USP-4,020,518 a buccal implant of which medicine is released by saliva; USP-3,679,360 topical gel; USP-3,339,546 bandages containing topical medicine; USP-3,964,164 plastic mass containing medicine; USP-3,219,527 medicated periodontal dressing; USP-3,698,392 topical dressing containing medicine dispersed in microparticulated carrier; USP-4,329,333 droplet of medicine microcapsulated; and USP-3,844,286 foam film devices containing medicine.
While collagen film containing tetracycline developed by Minabe etc., is a biodegradalde preparation of which effective concentration is prolonged over 10 days in palatal bursa of gingive, it has a disadvantage of causing immunoreaction due to hetero antigen-protein.
While filamentous devices containing medicine, described in USP-3,417, 179, USP-2,667,443, USP-2,748,781 and USP-3,942,539 and hollow fiber device described in USP-4,175,326, both made of cellulose acetate, are effective in inclusion of medicine but not in control of releasing medicine.
In case of hollow fiber, the elution of 95% of medicine is completed in 2 hours, while in case of
monolith fiber, that is completed in one day. Also, monolith fiber made of ethylene vinyl acetate polymer is excellent as a sustained release preparation because the elution of medicine is prolonged for 9 days. However, since the carrier is insoluble so that it can react as a physical promoter in inflammation reaction, and it should be removed after treatment due to its undegradability, they are disadvantageous to be used. As a filamentous biodegradable medicine, polyglycolinic acid fiber containing medicine is described in USP-3,991,766. Besides, there is soluble hydroxypropyl cellulose strip, as a soluble carrier, developed by Niguchi. Although there is not disadvantage of removing after treatment because of its high solubility, it is unsuitable for long-term therapy since the elusion of medicine is completed in 24 hours due to dissolution of carrier. Further, hydrophilic paste preparation to be injected to periodontal cyst with syringe containing tetracycline has been developed. However, the dependency between the clinical effect and change in concentration of tetracycline has not yet been determined.
SUMMARY OF THE INVENTION
Therefore, in order to solve the above described problems, the present invention has an object to provide an advanced biodegradable sustained release medicine carrier.
To attain the object described above, this invention provides a biodegradable sustained release preparation of which the core contains sodium alginate unit and medicine, and the surface thereof is coated with chitosan. Accordingly, the preparation of the present invention can maximize the inclusion effect of medicine into periodontal cyst and slowly release the medicine for a prescribed period by preparing microcapsules with polysaccharide.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 1. Figure 2 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 2.
Figure 3 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 3.
Figure 4 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 4.
Figure 5 is a graph showing the releasing pattern of medicine dependent upon content of medicine of Example 5.
Figure 6 is a graph showing the comparison of release of medicine from the biodegradable sustained release preparation in accordance with the present
invention to the release from a conventional product, Periocline.
DESCRIPTION OF THE PREFERRED EMBODIMENT Polysaccaride is non-toxic, nonimmunological and natural polymer, and attempts of using this polymer as a pharmaceutical carrier have been recently tried. Since it can be dissolved in vivo and degraded by hydrolysis or enzyme, it is excellent biodegradable material having a great possibility of being used as a graft.
Therefore, the present inventors prepared anionic polysaccaride microspheres containing medicine by using gelating power of polysaccaride and then coating thereof with a cationic polymer, i.e. chitosan to provide microcapsules.
At first, microspheres are prepared by gelation of a solution of sodium alginate with bivalent cation.
Then, the product is reacted with cationic polymer of chitosan, of which ionic character is counter to alginic acid, to form a film to make microcapsules.
The elution of medicine of the preparation produced by the present method is controlled by film of chitosan. After releasing medicine, chitosan is dissociated by enzyme in mouth such as lysozyme. The role of polysaccharide, i.e. sodium alginate as a unit of preparation is inclusion of medicine into the preparation, and the role of chitosan is controlling the release of medicine.
The concentration of chitosan is about 2% by weight/volume. If the concentration is far lower than 2% by weight/volume, it is impossible to control the release of medicine for 7 days, where the effect of the coated layer decreases by viscous chitosan if the concentration is far higher than 2% by weight/volume. The size of the microparticle containing medicine is desirably about 70 μm. If the size is far larger than 70 μm, injection from a container for applying the preparation into periodontal cyst is difficult, where the medicine releases in short period if the size is far smaller than 70 μm.
The medicine used in the preparation of the present invention includes tetracycline hydrochloride, tetracycline bases, minocycline hydrochloride, ibuprofen or flubiprofen, and, in particular, minocycline hydrochloride is desirable. The content of the above medicine is preferably 2% to 10% by weight each with respect to the weight of the final formulation. If the content is lower than 2% by weight, it is impossible to maintain the released concentration of medicine to MIC, where the medicine may cause toxicity if the content exceeds 10% by weight.
The present invention is illustrated in further detail by way of following examples, and it is to be understood that modifications of the present invention will be no doubt apparent to a person having ordinary skill in the art to which the invention pertains, within the spirit and scope of the present invention.
Example 1
A 2% by weight/volume solution of sodium alginate containing medicine was added dropwise to a 1.5% by weight/volume aqueous solution of calcium chloride by using a droplet extruser nozzle through which a compressed gas was passing. After dropping, the mixture was gellated for 5 minutes. Subsequent to washing and filtering the resultant gelated particles, collected microparticles were coated with 2% by weight/volume solution of chitosan for 10 minutes.
The medicine was minocycline hydrochloride, and the content of the above medicine was 2%, 5% or 10% by weight each with respect to the weight of the final formulations.
The experiment of releasing the medicine from the microspheres prepared was carried out by the following steps: 50 mg of microspheres put in a basket was added to 50 ml of HEPES buffer solution and the resultant mixture was shaked at 37 ± 0.5, 15 rpm; the samples were collected in a predetermined duration for 7 days and quantatively analysed by the use of UV spectrophotometer.
The result is shown in Figure 1. This graph shows the release pattern where the content of medicine was 2%, 5% or 10% by weight/volume each. It is found that the release of the medicine increases proportionally to the content of medicine. The initial rate of release increased with the increase of medicine content, and
then the release of medicine increased with constant rate.
Example 2 Coated microspheres were prepared in accordance with Example 1 but a 2% by weight/volume solution of sodium alginate without containing medicine. The coated microsperes were then immersed in a medicinal solution, and it was left alone for 24 hours and dried to make the content of medicine with respect to the final formulation become 2%, 5% or 10% by weight.
The result of experiment for the release of medicine is shown in Figure 2.
Example 3
Microspheres prepared in Example 2 were immersed in 0.5%, 1% or 2% by weight/volume solution of minocycline hydrochloride respectively so that the swelling load was carried out. The content of the medicine was made 2%, 5% or 10% by weight each with respect to the weight of the final formulation, dependent upon the concentration.
The time period for swelling load was 24 hours.
Then, the microparticles encapsulating medicine was coated with a 2% by weight/volume solution of chitosan.
The result of experiment for the release of medicine is shown in Figure 3.
Example 4
A solution of sodium alginate containing medicine was emulsion-dispersed in organic solvent containing a surfactant. To the resultant dispersion was added dropwise a solution of calcium chloride so that microparticles of gel was formed. The organic solvent was a 3:1 mixture of hexane and chloroform, and the surfactant used was Span, a surfactant of sorbitan monostearate. The concentration of the surfactant was 0.4% by weight/volume with respect to the dispersion medium. The resultant microparticles were collected, washed and filtered. Then a 2% by weight/volume solution of chitosan was added thereto to form a coating.
The medicine was minocycline hydrochloride and the content of the above medicine was 2%, 5% or 10% by weight each with respect to the weight of the final formulation.
The result of the experiment for release of medicine is shown in Figure 4.
Example 5
According to Example 4, microparticles of sodium alginate without containing medicine were prepared and these were immersed in each medicinal solutions with different concentration to be swelling loaded.
The medicine was minocycline hydrochloride and each content of the above medicine was 2%, 5% or 10% by weight with respect to the weight of the final formulations. The time period for swelling load was 24
hours. After washing and filtering, the microparticles encapsulating the medicine were coated with a 2% by weight/volume solution of chitosan.
The result of the experiment for release of medicine is shown in Figure 5.
As can be seen from the result of the experiment for release of medicine for 7 days, where the conventional product, Periocline shows maximum release rate in first day and the increase of release was extremely weak thereafter, the biodegradable sustained release preparation according to the present invention shows gradual increase of releasing rate from the period after first day to the seventh day (See Figure 6) .
Therefore, the present invention provides a biodegradable sustained release preparation which can slowly release the antibiotic in periodontal cyst in a long-term period.
Claims
1. A biodegradable sustained release preparation for external use for treating periodontitis, characterized in that a core contains sodium alginate and medicine, and the surface thereof is coated with chitosan.
2. A biodegradable sustained release preparation in accordance with claim 1, characterized in that the content of said medicine is 2 - 10% by weight with respect to the weight of the final preparation.
3. A method for preparing a biodegradable sustained release preparation for external use for treating periodontitis, characterized in that said core is coated by ionic reaction between an anion thereof and a cation of said chitosan.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR19940028496 | 1994-11-01 | ||
KR9428496 | 1994-11-01 | ||
PCT/KR1995/000132 WO1996013253A1 (en) | 1994-11-01 | 1995-10-16 | Biodegradable sustained release preparation for treating periodontitis |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0806944A1 true EP0806944A1 (en) | 1997-11-19 |
Family
ID=19396807
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95934323A Withdrawn EP0806944A1 (en) | 1994-11-01 | 1995-10-16 | Biodegradable sustained release preparation for treating periodontitis |
Country Status (6)
Country | Link |
---|---|
US (1) | US5855904A (en) |
EP (1) | EP0806944A1 (en) |
JP (1) | JPH11509167A (en) |
KR (1) | KR960016882A (en) |
CN (1) | CN1098105C (en) |
WO (1) | WO1996013253A1 (en) |
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GB9905136D0 (en) * | 1999-03-06 | 1999-04-28 | Danbiosyst Uk | Surface modification of lamellar particles |
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ATE258417T1 (en) * | 1999-07-02 | 2004-02-15 | Cognis Iberia Sl | MICRO CAPSULES - I |
DE59912559D1 (en) * | 1999-07-02 | 2005-10-20 | Cognis Ip Man Gmbh | Microcapsules - III |
ES2213948T3 (en) | 1999-07-02 | 2004-09-01 | Cognis Iberia, S.L. | MICROCAPSULES II. |
ES2247997T3 (en) * | 2000-09-01 | 2006-03-16 | Cognis Ip Management Gmbh | COSMETIC PREPARATION IN THE FORM OF A BAR. |
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CN100453119C (en) * | 2006-03-16 | 2009-01-21 | 浙江大学 | Preparing process of bioadhesive chitosan particle for embedding and transferring active medicine |
CN100444896C (en) * | 2006-06-29 | 2008-12-24 | 上海交通大学 | Chitin nanometer granule for programmable releasing various kinds of medicine, and its prepn. method |
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- 1995-07-07 KR KR1019950019947A patent/KR960016882A/en not_active Application Discontinuation
- 1995-10-16 EP EP95934323A patent/EP0806944A1/en not_active Withdrawn
- 1995-10-16 JP JP8514461A patent/JPH11509167A/en active Pending
- 1995-10-16 US US08/817,552 patent/US5855904A/en not_active Expired - Fee Related
- 1995-10-16 WO PCT/KR1995/000132 patent/WO1996013253A1/en not_active Application Discontinuation
- 1995-11-01 CN CN95118231A patent/CN1098105C/en not_active Expired - Fee Related
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Title |
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KR960016882A (en) | 1996-06-17 |
JPH11509167A (en) | 1999-08-17 |
CN1131042A (en) | 1996-09-18 |
CN1098105C (en) | 2003-01-08 |
US5855904A (en) | 1999-01-05 |
WO1996013253A1 (en) | 1996-05-09 |
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